Single Cell Analysis of Retrotransposition and Genetic Mosaicism during Stem Cell-based Neurogenesis

Bona fide human neurons can now be studied directly in ways that have never before been possible. This is due to the ability of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) to differentiate into any cell in the body. However, it is critical that we learn both the similarites and differences between these two types of stem cells with regard to how well hESC-derived and hiPSC-derived human neurons resemble true human neurons. In addition, patient-derived hiPSCs provide a new avenue to help understand how human neurons give rise to neuropsychiatric disorders, such as schizophrenia. Whereas most healthy organs are made up of cells with identical genomes, it has recently become clear that the human brain is composed of many neurons that have unique variants of that individual's genome. Genomic diversity among an individual's neuronal genomes is brought about, in part, through the action of L1 retrotransposons. L1 retrotransposons are "jumping genes" that copy-and-paste themselves into new places in different cells through a process known as retrotransposition. Some level of L1 retrotransposition is normal and may contribute to individuality, particularly between identical twins. However, too much retrotransposition has been associated with neurological disorders. We propose to study L1 retrotransposition in hESC- and hiPSC-derived neurons from different individuals alongside hiPSC-derived neurons from schizophrenia patients. The proposed research will determine the extent to which L1 retrotransposition in stem cell-derived neurons recapitulates L1 activity during normal human development, and examine roles for retrotransposition in bringing about neural connectivity abnormalities observed a newly developed hiPSC-based model of schizophrenia.

Statement of Benefit to California:

Neuropsychiatric diseases affect millions of Californians directly, and untold more indirectly through the additional stess placed on a patient's family and loved ones. In addition, neuropsychiatric patients are at increased risk of homelessness and substance abuse that places additional burden broadly on all Californians. In passing Proposition 71, Californians asked California's scientists to advance stem cell research in meaningful ways. Neurons derived from stem cell are poised to be game-changers toward understanding and treating neuropsychiatric disease; thus, the proposed research promises to benefit all Californians by advancing our general understanding of stem cell-derived neurons, and by specifically investigating the neurodevelopmental basis of schizophrenia.